Chronic exposure of the skin to ultraviolet light (UVB) is a major known cause of nonmelanoma skin cancer as demonstrated by epidemiological evidence and by the tight correlation between cancer development in humans and that of the mouse models of UVB-initiated cancer. Although UVB-induced skin cancers are widely believed to originate from the transformation of epidermal or hair follicle stem cells, recent demonstration that gastric cancer originates from bone marrow derived cells (BMDCs) challenges this dogma. The objective of this proposed investigation is to determine the relative contributions of hair follicle stem cells and BMDCs to developing skin tumors in the mouse UVB model of cutaneous carcinogenesis. Our hypothesis is that both hair follicle stem cells and BMDCs are important target cells in skin cancer development and progression. Our method of approach will be to transplant genetically labeled BMDCs ("green cells") to lethally irradiated Krt1-15CrePR1;R26R female mice that express beta- galactosidase in hair follicle stem cells and their progeny following induction with RU486 ("blue cells"). At intervals during chronic UVB exposure, we will then assess developing epithelial lesions for cells of donor origin (expressing EGFP and the Y chromosome) vs. hair follicle stem cell origin in skin sections and harvested cell preparations from skin and tumors. Then we will determine the relationship of both of these populations to the development of mutant p53 patches, as wells their relationship to apoptotic bodies (sunburn cells) and other markers of cell death. These experiments will not only determine the respective contributions of BMDCs and hair follicle stem cells to developing tumors, they will also set the stage for defining the relationship of skin tumor initiating cells to tumor stem cells. These experiments also have the potential to change current thinking on the mechanisms of skin cancer development and how such cancers are diagnosed and treated. PUBLIC HEALTH RELEVANCE: Chronic exposure of the skin to sunlight (UV light) is a major known cause of skin cancer. Although UV-induced skin cancers are widely believed to originate from epidermal or hair follicle stem cells, a recent report that stomach cancer can originate from the transformation of bone marrow derived cells challenges this dogma. The objective of the research proposed here is to determine the relative roles of bone marrow derived cells and hair follicle stem cells and their progeny to developing skin tumors in the mouse UV model of skin cancer. The approach and results of this study are relevant to human health in that they will not only determine the respective contributions of bone marrow derived cells and hair follicle stem cells to skin cancer, they will also have the potential to change current thinking on the way that skin cancer is diagnosed and treated in the clinic.